The Central Theme of this program is to advance biology of the Natriuretic Peptide System (NPS) leading to innovative therapeutic strategies for cardiovascular disease. Our working hypothesis is that the natriuretic peptides (NPs) (ANT and BNP which bind to the particulate guanylyl cyclase (pGC) natriuretic peptide A receptor [NPR-A] and CNP which binds to the pGC NPR-B receptor and which all function via cGMP) serve as autocrine, paracrine and circulating factors whose biological properties mediate protective actions upon cardiovascular function and structure to complement known actions on the kidney and vasculature. This provides the rationale for their further development as novel therapeutic agents for the treatment of cardiovascular disease. Four projects are proposed with 2 cores and involve molecular and cell biology, mouse and large animal integrative physiology, cell and gene therapy and General Clinical Research Center (GCRC) based human physiology. Project 1 proposes an in-depth application of integrative physiology in novel mouse models of genetically modified natriuretic peptide (NP) receptor function to advance our understanding of the NPS and its physiologic and therapeutic potential in the modulation of cardiomyocyte structure and function. Here there is special emphasis on NPR-A receptor regulation of diastolic function with applicability to the therapeutics of diastolic heart failure. Project 2 defines an effective and novel strategy of chronic NP therapy with native and synthetic Mayo designed NPs to prevent cardiac fibrosis in a clinically relevant large animal model of hypertensive heart disease (HHD) as well as pursuing an alternative cGMP strategy targeting soluble GC with a novel sGC stimulator not dependent upon Nitric Oxide. In addition, the mechanism by which the NPs and cGMP inhibit cardiac fibroblast proliferation will be elucidated. Project 3 shifts from HHD in Projects 1 and 2 to a large animal model of CHF developing a strategy of cell and gene therapy to delay the progression of CHF. While NP therapy with BNP has been approved in humans for acute CHF, a high priority is to apply new technologies to define long-term peptide delivery in cardiovascular disease. In Project 4, importantly extends our laboratory-based research to the understanding of the physiology and therapeutic potential of the NPs to the treatment of human disease, focusing on BNP therapy.